The majority of prostate cancers (PCa) are androgen dependent and respond to androgen ablation therapy, but most relapse with disease that is clinically androgen independent. However, the androgen receptor (AR) is still expressed in androgen independent prostate cancer (PCa) and there appears to be selective pressure for AR gene amplification and mutations that augment AR activity. These observations suggest that the AR remains a therapeutic target in androgen independent PCa and that our current hormonal therapies may be inadequate to suppress AR function. To test this hypothesis we have developed androgen independent PCa cell lines from the CWR22 xenograft that are also AR antagonist (bicalutamide) resistant, but express AR and prostate specific antigen, consistent with the phenotype of clinical androgen independent Pca. This project will use these and additional xenografts to assess the role of the AR in androgen independent PCa and to develop new therapies that target the AR in androgen independent PCa. Xenografts and clinical samples will then be examined by oligonucleotide arrays to determine mechanisms of androgen independent growth and identify groups of genes whose expression predicts responses to AR directed therapies.
The specific aims are to 1) determine whether the AR is active and necessary for tumor growth or survival in androgen independent PCa cell lines, 2) determine whether the AR contributes to the in vivo growth of a series of androgen independent PCa xenografts, and 3) subset androgen independent PCa xenografts based upon responses to therapy and compare with clinical samples using oligonucleotide microarrays. Taken together, the results from these experiments will establish whether the AR is active and a therapeutic target in androgen independent PCa, identify mechanisms of androgen independent growth, and identify subsets of patients likely to respond to further AR directed therapy.
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